Projects

Treatment effect estimation for neuropsychiatric disease trials in the presence of non-compliance

Aims:
In clinical studies concerned with the development of new medicinal products for treating neuropsychiatric diseases, estimation of the treatment effect may be substantially impeded by the great number of patients discontinuing or switching therapy in the course of the study. Considering the general framework, some of these patients could be followed up until the end of the study. Incorporating this data appropriately into the statistical analysis would allow assessing the treatment effect under real conditions. This is to be distinguished from the “ideal“ treatment effect, in which case it is assumed that all patients have taken the medicine as prescribed.

Methods:
Considering potentially different patterns of discontinuing or switching treatment, and including the data collected after discontinuation or switch, various statistical methods for the estimation of treatment effects are developed and compared according to their validity and efficiency.

Outcome and conclusions:
Our previous analyses show that the choice of a valid analysis strategy depends essentially on differentiating between the “ideal” treatment effect if all patients have taken the medication as prescribed and the treatment effect achieved in actually occurring treatments. Estimation of treatment effect on the basis of the actual treatment process should include the data obtained after discontinuation or switch. For an overall picture of treatment effects, it should generally be attempted that after discontinuation/switch as many patients as possible are followed up until the end of the study.

Surrogate endpoint validation for count data with application in drug development for Multiple Sclerosis

Dorothee Wirtz, Markus Neuhäuser*, Jörg Zinserling, Norbert Benda

Aims:
Long lasting clinical studies and high patient numbers are often necessary to detect treatment effects in relevant endpoints likewise survival (oncology). One possibility to keep studies shorter is the use of surrogate endpoints in phase II studies measurable at an earlier point of time and reflecting the relevant endpoints.
In pharmaceutical studies on multiple sclerosis the number of lesions in the CNS is referred to as surrogate for relapse rates within a defined period of time, even though the correlation is low at patient level. A higher correlation was claimed at study level by some authors (Sormani et al. [2]).

Methods:
In this context of count data, we evaluate various methods for the validation of surrogate endpoints at study level using mixed models and simplified hierarchical models. These methods have been derived from those developed for normally distributed data by Burzykowski et al. [1] and Tibaldi et al. [3].

Outcome and conclusions:
The correct evaluation of surrogate endpoints is essential for drawing reliable conclusions from surrogates to the actually relevant endpoints. The results will also be useful for a better assessment of multiple sclerosis studies presented in authorisation procedures.